Kavalactone product

ABSTRACT

The present invention is a method for enhancing the efficacy of an active ingredient in a human comprising: administering to said human a product comprising: a kavalactone component and an active ingredient, wherein said active ingredient is selected from the group consisting of a therapeutic, a pharmaceutical, a nutraceutical and a botanical, and wherein said kavalactone component comprises a methysticin component, a dihydromethysticin component, a desmethoxyyangonin component, a yangonin component, a dihydrokavain component, and a kavain component, and wherein said kavalactone component is between about 0.1% to about 75%, by mass, of said product.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority as a continuation-in-part under35 U.S.C. § 120 to U.S. patent application entitled “ImprovedKavalactone Profile” filed Oct. 18, 2003, Ser. No. 10/273,943; whichclaimed priority as a continuation-in-part under 35 U.S.C. § 120 to U.S.Patent Application entitled “A Method Of Producing A Processed KavaProduct Having An Altered Kavalactone Distribution And Processed KavaProducts Produced Using The Same”, filed Oct. 3, 2002, which claimedpriority under 35 U.S.C. § 119 to U.S. Provisional Patent ApplicationSerial No. 60/326,928 entitled “Methods For Processing Kava Root (PiperMethysticum) And Kava-Derived Products Generated By These Methods HavingControllable Kavalactone Ratios”, filed on Oct. 3, 2001, and U.S.Provisional Application Serial No. 60/369,889 entitled “Dry FlowableKava Extract Powder And Fast-Dissolve Kava Extract Composition For OralDelivery”, filed on Apr. 3, 2002. The entire contents of theseapplications are hereby expressly incorporated by reference.

FIELD OF THE INVENTION(S)

[0002] This invention is related to methods for processing kava toproduce a kava extract with particular kavalactone concentrationprofile, a processed kava product, such as a dry flowable kava extractpowder, and the use of such a powder in a rapid-dissolve tablet for oraldelivery. Furthermore, this invention relates to a particularkavalactone concentration profile. Further yet, this invention relatesto a kavalactone product used as an additive to potentiate and/orenhance the action of therapeutics, pharmaceuticals, nutraceuticals, orbotanical extracts.

BACKGROUND

[0003] Kava plants, a type of pepper plant also known as Pipermethysticum, are generally found in Polynesia, Melanesia, andMicronesia. The kava plant contains high concentrations of kavalactones(sometimes referred to as kavapyrones), including kavain, methysticin,yangonin, dihydromethysticin, desmethoxyyangonin, and dihydrokavain, andhas been used as an herbal medicine. The prized part of the kava plantis the root system because it contains the highest concentrations of theactive kavalactones. Kavalactones are also found in other parts of theplant. General information about kava plants can be found in VincentLebot, et al., “Kava The Pacific Elixir, The Definitive Guide to itsEthnobotany. History, and Chemistry”, Inner Traditions Intl. Ltd. (March1997).

[0004] After a kava plant is harvested, the root is conventionallyprocessed to generate a consumable product. In conventional andhistorical methods, the root is dried and ground to a powder. Thispowder contains not only the kavalactones but also plant oils, resins,and other substances. The powder can be mixed with water to form abeverage. The resinous ground dried root can also be packaged intocapsules or other forms of delivery.

[0005] The effects of ingesting kava root extract will vary from personto person. Common effects include a state of relaxation and a reductionin muscle tenseness. Kava root has also been used to help sufferers ofinsomnia. It can also produce a mild state of euphoria. The ratios ofthe various kavalactones in the consumed product has a large impact onthe effect experienced by the user.

[0006] There are a large number of different kava cultivars, each ofwhich has differing ratios of the different kavalactones. Throughhistorical knowledge and experimentation, various kava cultivars havebeen classified according to their effect, such as “daily” or “one-day”,“custom”, “two-day”, “medicinal”, and “no drink”. “Daily” kava cultivarsare generally consumed daily and have relatively short-term effects.“Custom” kava cultivars tend to be used for ritual and ceremonialpurposes. “Two-day” kava cultivars tend to have pronounced physiologicaleffects and are known as “two day” because the drinker is usuallyaffected for two days. “Medicinal” kava cultivars are specific for thetreatment of ailments like rheumatism. “No Drink” kava cultivars are notrecommended for consumption because they tend to induce nausea and otherundesirable effects.

[0007] More recently, there have been concerns associating kava withoccurrences of liver damage, although these reports are primarilyanecdotal. Studies done in the 1970s and 1980s have found that “two day”kava cultivars have particularly high concentrations of methysticin anddihydromethysticin. These kavalactones contain a methylenedioxyphenylfunctional group which, when activated through metabolic activity, formsintermediary compounds that can inactivate multiple P450 enzymes. Thereare some suggestions that inhibition of P450 enzymes can interfere withthe metabolism of many pharmaceuticals. The solution proposed in theprior art is the development of new kava cultivars with reduced amountsof methysticin and dihydromethysticin and increased kavain content.

[0008] One of the most highly prized kava cultivars is a one-daycultivar that grows in Vanuatu. Relative to other cultivars, thiscultivar is naturally low in methysticin and dihydromethysticin and hasa proportionally higher concentration of kavain. However, this cultivaris not widely grown or available and most commercially availablecultivars have increased levels of methysticin and dihydromethysticinand lower concentrations of kavain. Although breeding of new cultivarsthat can be widely grown and which have lower concentrations ofmethysticin and dihydromethysticin and increased concentrations ofkavain is possible, this can be a time consuming process and is notassured of success. In addition, the kavalactones suspected of producingtoxic effects when consumed by humans are also toxic to various insectsand microorganisms, such as fungi. Thus, the hardiest cultivars aregenerally those which are least suitable for human consumption.

[0009] In a kava extraction process, the rate at which variouskavalactone components are extracted varies according to the extractionsolvent and extraction conditions used. However, kava root extracts areconventionally sold based upon total kavalactone content. Thus, thefocus of conventional commercial extraction techniques has been toextract as much of the kavalactone content from the root source aspossible and knowledge regarding different rates of extraction fordifferent kavalactones is used to adjust the extraction process orselect appropriate extraction steps to provide for the greatest totalkavalactone extraction.

[0010] Various extraction techniques have been used to process kavaroot. Such techniques include the use of supercritical carbon dioxide(CO₂) extraction, fluorocarbon extraction, and the use of various otherorganic and non-organic solvents to remove the kavalactones from thedried root. The resulting bulk extract is in the form of a paste.

[0011] Supercritical CO₂ processes have been found to extract thelargest quantity of kavalactones from the root and thus conventionalpractice has been to focus on the use of supercritical CO₂ to extractall of the kavalactones from the root in the production of kavaextracts. As will be appreciated, bulk extracts of substantially all ofthe kavalactones in the root will generally contain kavalactones in thesame or nearly the same proportions as present in the source root.Because of the differing effects produced by variations in thekavalactone ratios of different cultivars, producers of such kavaproducts are limited to specific kava cultivars as source materials inorder to produce a kava product that produces a desired effect.

[0012] To the extent that the distribution profile of the variouskavalactones in the extract have been of concern, conventional practiceis to use additional processing steps, such as high pressure liquidchromatography (HPLC), to extract individual kavalactones. For example,HPLC and other chromatographic techniques, such as “flash”chromatography, have been used to process bulk kava extracts to isolateindividual kavalactones. This process is cumbersome to implement andrequires the use of machinery that is bulky and expensive to operate.Methods for extracting and purifying kava, including supercritical CO₂extraction and chromatography, are discussed in PCT publication WO00/72861 to Martin et al. entitled “Pharmaceutical Preparations ofBioactive Substances Extracted from Natural Sources.”

[0013] It would be advantageous and is an object of the presentinvention to provide a method of processing kava to provide an extractof kava as a paste, powder, or in other forms, and which allows thekavalactone profile to be altered during processing so as to havereduced levels of methysticin and dihydromethysticin and increasedlevels of kavain and dihydrokavain. It would be additionallyadvantageous if such techniques allowed the production of a processedkava product that had a kavalactone profile similar to (or improvedupon) that of the most preferred “one-day” cultivars from Vanuatu byusing a kava feedstock from a less desired cultivar. There would be yeta further advantage if such an altered-profile kava product could beproduced using a minimal number of processing steps and withoutrequiring additional processing, such as via chromatography, to isolateeach individual kavalactone from the extract and then recombine theisolated kavalactones as appropriate. Still another advantage would beartificially producing a material having a desired kavalactone profile.

[0014] There has been widespread use of bulk kava paste extracts asdietary supplements, e.g., mixed in drinks or packaged in capsules.Because kava paste is not always well suited for processing intoconsumable form or for distribution, e.g., as a dietary supplement, itwould also be advantageous to produce a dry flowable kava powder. Thepowder can be distributed as is or further processed, e.g., to producekava tablets.

[0015] When consumed, kava is typically swallowed. The kavalactones thenpass through the stomach and intestines as they are absorbed into thebloodstream. It can take a relatively long time for the body to processkava and the effect of the ingested kavalactones can then be furtherdiminished as the compounds are processed by the liver. It wouldtherefore also be advantageous to deliver kava in the form of arapid-dissolve tablet which would permit the kavalactones to be absorbedorally. It would also be advantageous to use an improved kavalactoneproduct as an additive to potentiate and/or enhance the action oftherapeutics, pharmaceuticals, nutraceuticals, or botanical extracts.

SUMMARY OF THE INVENTION(S)

[0016] These and other objectives are met by use of the present methodsof processing kava to produce a kava product, such as a paste, resin,oil, or a powder suitable for use in a fast dissolve tablet and otherapplications, and which as a kavalactone profile that is altered fromthe profile of the kava feedstock. The present methodologies also allowthe distribution of kavalactones to be altered or adjusted to achieve aparticular kavalactone profile wherein the effectiveness of the kava canbe enhanced or the negative effects reduced. Various other novel kavaextract compositions are also presented.

[0017] Preferably, a two stage process is used. First, the kavalactonesare extracted from the kava root material to form a kava paste.Preferably, the paste is generated using liquid CO₂ extractiontechniques. However, under some conditions, supercritical CO₂ extractiontechniques can be used. During processing, an initialpressurization/depressurization step can also be included to increasethe rate at which the kavalactones can be extracted from the rootstock.The output of the first processing step is a viscous paste, oil, and/orresin.

[0018] The paste can then be subjected to a second or further refinementstages, if desired, to further purify the kavalactones and produce ahighly refined paste extract. Preferably, the parameters of the secondprocessing stage (and possibly the first stage as well) are selected toalter the kavalactone distribution in the raw material in order toachieve a predetermined distribution and concentration of the variouskavalactones without the need of chromatography or other techniquesconventionally used to extract individual kavalactones.

[0019] Advantageously, the use of the extraction techniques according tothe various embodiments of the invention thus allows high qualitykavalactone having a desired profile, such as reduced levels ofmethysticin and dihydromethysticin and increased levels of kavain anddihydrokavain, to be easily and economically produced from a kavafeedstock, such as dried ground root, which has an undesired kavalactoneprofile. In a particular example, an undesired kava stock, such as a“two-day” or “no-drink” cultivar, can be processed to produce a kavaextract having a kavalactone distribution profile which is comparable tothe most desired “one-day” Vanuatu cultivar.

[0020] For example, processing of kava using CO₂ at pressures of 1100psi or greater and at a temperature greater than 31° C. places the CO₂in a supercritical state and will extract on the order of 80% to 100% ofthe kavalactones in the source. However, the extraction rate of thevarious kavalactones are fairly similar and the resulting extract willhave a kavalactone profile that is similar to, if not identical to, thatof the feedstock. (However, with careful control over the extractionparameters, subtle changes in the kavalactone profile can be made usingsupercritical CO₂ extraction.)

[0021] In contrast, it has been found that processing the kava feedstockusing liquid CO₂ at pressures of between about 1100 psi to about 1800psi and temperatures between about 0° C. and about 25° C. producespreferential extraction wherein methysticin and dihydromethysticin areextracted at a considerably slower rate than other kavalactones. It hasbeen further found that processing at between about 1100 to about 1500psi at temperatures between about 5° C. and about 10° C. also producesan increased relative concentrations of kavain and dyhydrokavainrelative to other kavalactones in the extract.

[0022] Through use of the present techniques, kava extracts can beproduced having a kavalactone profile that is unlike those found innature and the profile can be tailored to meet particular designconsiderations. Preferably, the kava product has kavalactone propertiesthat have been selected to be low in the combined weight percentage ofmethysticin (M) and dihydromethysticin (DHM), low in the combined weightpercentage of desmethoxy yangonin (DMY) and yangonin (Y), and high inthe combined weight percentage of kavain (K) and dihydrokavain (DHK).The preferred kava product can be characterized according to one or moreof the following attributes: (a) a combined weight percentage of the sixmajor kavalactones methysticin (M), dihydromethysticin (DHM), yangonin(Y), desmethoxyyangonin (DMY), kavain (K), and dihydrokavain (DHK) ofbetween about 20% to a maximum of about 90%; (b) a combined weightpercentage of M and DHM between about 5-15% to about 29%; (c) a ratio ofY to DMY by weight, expressed as the logarithmic function10*LOG10(Y/DMY) in dB units, from about −1 to about 2; (d) a ratio ofDHK to K by weight, expressed as the logarithmic function10*LOG10(DHK/K) in dB units, from about −4 to about 1; (e) a combinedweight percentage of Y and DMY between about 5% to about 20-25%, and (f)a combined weight percentage of flavokavain A and flavokavain B ofbetween about 0.3% to about 3%.

[0023] Alternatively, the kava product may be synthetically produced bycombining the particular kavalactones in the desired weight ratios. Theresulting material preferably has a kavalactone profile having at leastone of the following characteristics: a) a combined weight percentage ofM and DHM less than about 15% of the total weight of the profile, b) acombined weight percentage of DMY and Y less than about 8% of the totalweight of the profile and c) a combined weight percentage of K and DHKis greater than about 70% by weight of the kavalactone profile.

[0024] Once a suitable kava paste, resin, or oil, is provided, it canthen processed for various uses. For direct ingestion, for example, apaste can be sweetened and flavored. In addition or alternatively, thepaste can be mixed with other dietary supplements, such as the verysweet tasting herb Stevia, or other herbal or non-herbal ingredients.

[0025] A kava paste can also be further processed to prepare a highquality dry flowable powder which can be used, for example, to producean ingestible kava tablet. In a first embodiment, a kava paste iscombined with a carrier, such as maltodextrin, dextrose, or starches andmixed with a suitable solvent, such as ethyl alcohol or water. Themixture is then spray dried to produce a powder having grains comprisedof kava extract and the carrier. In a second embodiment, an emulsion ofkava paste is formed in water or ethyl alcohol using, e.g., magnesiumcarbonate, magnesium carbonate+silica (at up to about 2% by weight),whey protein, maltodextrin, carboxymethylcellulose and/or other suitablematerials. The emulsion is then dried and powdered. In a thirdembodiment, the extract is processed with supercritical CO₂ and acarrier, such as maltodextrin, dextrose, or starches and then subjectedto a rapid decompression of the supercritical fluid. As the fluidevaporates, the extract and kava are deposited as micro-sized particles.

[0026] The resulting powder, preferably having a preselected ratio ofkavalactones, can then be formed into a tablet that, when placed in themouth, dissolves rapidly over a period of between about 5 to about 180seconds and preferably in about 15 to about 60 seconds. A tabletingpowder can be formed by combining between about 25% to about 60% byweight of the powdered kava extract with between about 30% to about 60%by weight of a dry water-soluble absorbant such as magnesium carbonate,or a diluent, such as lactose. Other dry tablet additives, such as oneor more of a sweetener, flavoring and/or coloring agents, a binder, suchas acacia or gum arabic, a lubricant, a disintegrant, and a buffer, canalso be added to the tableting powder. Preferably, the dry ingredientsare screened to a particle size of between about 80 to about 100 mesh.

[0027] To form the tablets, the tableting powder is then wet with asolvent, such as alcohol or water, until it achieves a doughyconsistency. The paste is then molded or pressed into tablets which aredried and packaged. The tablets can be of any suitable size, shape, andweight. Preferably, the tablets are formed into disks or wafers having adiameter of between about ⅛ and about ½ inch, a thickness of betweenabout 0.08 and about 0.2 inch, and a weight of between about 50 mg toabout 1000 mg. The tablets are preferably homogeneous. However, they canalso be formed of regions of kava extract composition separated bynon-kava extract regions in periodic or non-periodic sequences as may bedesired.

[0028] An improved kavalactone product may also used as an additive topotentiate and/or enhance the action of therapeutics, pharmaceuticals,nutraceuticals, or botanical extracts such that a lower dosage of thechosen therapeutic, pharmaceutical, nutraceutical, or botanical extractcan be used or administered as a dose. The mass percentage of the sum ofthe six kavalactones: methysticin, dihydromethysticin, kavain,dihydrokavain, yangonin, and desmethoxyyangonin, in relation to thetotal mass that includes the particular active therapeutic,pharmaceutical, nutraceutical, or botanical extract can be from 0.1% to75% of the total mass.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The following detailed description of the preferred embodiment(s)will be better understood with reference to the following figures inwhich:

[0030]FIG. 1 is a plot of total kavalactone weight percentages measuredin the lateral roots for five usage classes of Vanuatu kava cultivars:Daily, Custom, Two-day, Medicinal and No Drink;

[0031]FIG. 2 is a plot of Methysticin+dihydromethysticin weightpercentages measured in the lateral roots for five usage classes ofVanuatu kava cultivars;

[0032]FIG. 3 is a plot of average dihydrokavain+kavain vs.yangonin+desmethoxyyangonin kavalactone concentration ratios measured inthe lateral roots for various kava cultivars and extracts; and

[0033] FIGS. 4-7 show plots of relative kavalactone concentrations fordifferent kava cultivars and show changes in the kavalactone profileintroduced during processing according to the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

[0034] To better appreciate the utility of the present invention, it isuseful to present data describing the differences between the total andrelative amounts of various kavalactones in a variety of kava cultivars.The HPLC measurements for kava cultivars are taken from V. Lebot's andJ. Levsque's paper in Allertonia (1989) entitled, “On The Origin AndDistribution Of Kava (piper methysticumforst. F., piperaceae): APhytochemical Approach”. Lebot's and Levesque's procedure for theextraction and analysis of total kavalactone weight percentages andkavalactone concentration spectra for kava cultivars consisted of thefollowing steps: First, select only the lateral roots of a kava plantthat reached the age of two years. Next, dry lateral roots in an oven at60-80° C. for eight hours, and then grind the roots into powder. Then,perform a six hour Soxhlet extraction of powdered root using chloroformas the solvent. Finally, analyze the chloroform extract using HPLC.

[0035] Note that Lebot and Levesque used only the lateral roots tomeasure the kavalactone concentration spectrum for a given kavacultivar. This is important because different parts of the kava plant(e.g., rhizome, stem, leaves) have different kavalactone concentrationspectra, as well as different total kavalactone weight percentages.Total kavalactone weight percentage is highest in the lateral roots, anddecreases towards the aerial parts of the plant (pg. 67, Lebot, Merlin,Lindstrom, Kava-The Pacific Elixir, 1997). Lebot (1988) found in Vanuatukava cultivars that when the total kavalactone weight percentage wasabout 15% in the lateral roots, it dropped to about 10% and 5% in therhizome and basal stem, respectively. Lebot, et al (1997) on pp. 74-75report that K and DMY are the dominant kavalactones in the rhizome,whereas DHK and DHM tend to be the kavalactones with the highestconcentrations in the leaves. In summary, the kavalactone concentrationspectrum and total kavalactone weight percentage for a given kavacultivar can be determined by a number of factors, which include age ofthe plant, method of extraction, as well as the part of the plant.

[0036] 66 of the 67 Vanuatu cultivars identified in Table 2 in Lebot andLevesque (1989) were analyzed (33 Daily, 11 Custom, 14 Two-day, 4Medicinal, and 4 No Drink cultivars). Also analyzed were 26 of the 27Fijian kava cultivars from Table 6 in Lebot and Levesque (1989). Lebotand Levesque did not classify these cultivars according to the systemdescribed above. HPLC was used to determine the total kavalactone weightpercentages and kavalactone concentration spectra for the varioussamples.

[0037]FIG. 1 presents a plot of the total kavalactone weight percentagesmeasured by Lebot and Levesque (1989) in the lateral roots for the fiveusage classes of Vanuatu kava cultivars: Daily (D), Custom (C), Two-day(T), Medicinal (M), and No Drink (N). As will be appreciated, the totalkavalactone weight percentage does not uniquely identify the type ofkava cultivar, e.g., there are several D, C, T and M kava cultivars withtotal kavalactone weight percentages in the range of 11-12%. FIG. 1 alsoshows that the selection of a kava cultivar with a very low totalkavalactone percentage does not mean that it has the least effectbecause the class of No Drink kava cultivars has the lowest averagetotal kavalactone concentration. Accordingly, kava cultivars that havehigh concentrations of desirable kavalactones may also contain highconcentrations of undesirable kavalactones, making these cultivarsunsuitable for use in producing consumable kava products without firstaltering the profile of the kavalactones.

[0038]FIG. 2 is a bar graph plotting number of Vanuatu kava cultivarsvs. the combined M+DHM weight percentage measured by Lebot and Levesque(1989) in the lateral roots for the D, C, T, M and N classes of kavacultivars described for FIG. 1. Table 1 below summarizes the M%+DHM%averages for the five usage classes: TABLE 1 Average Weight Percentageof Methysticin and Dihydromethysticin in Lateral Roots for the FiveUsage Classes of Vanuatu Kava cultivars Kava Cultivar Usage ClassAverage M % + DHM % Daily 25 ± 4%  Custom 33 ± 9%  Two-day 39 ± 6% Medicinal 33 ± 13% No Drink 57 ± 10%

[0039]FIG. 2 and Table 1 indicate that the frequency of use for a kavacultivar is proportional to the M%+DHM%, with the Daily kavas having thelowest average of 25±4%, the Two-day kavas are 14% higher at 39±6%, andthe No Drink kavas have the highest M%+DHM% at 57±10%. Thus, the higherthe M%+DHM% for a Vanuatu kava cultivar, the less frequent its use.

[0040] Moreover, M%+DHM% has been found to be proportional to the degreeof induced nausea, which could help explain why frequency of use dropswith increasing M%+DHM%. In particular, Lebot, et al (1997) report onpg. 78 that DHM is a major component of Two-day (or tudei) kavas thatfrequently produce nausea. According to the work of the Meyer group inFreiburg, the M and DHM kavalactones are absorbed the slowest in thegastrointestinal tract. The strong anticonvulsive and muscle relaxantaction of M and DHM (see Meyer group work) combined with the fact that Mand DHM remain for longer periods of time in the gastrointestinal tractare consistent with the induction of nausea resulting from kavapreparations containing high percentages of M and DHM.

[0041] The relationships between M%+DHM% and Vanuatu kava cultivar usagepresented in FIG. 2 and table 1 above are important steps in classifyingVanuatu kava cultivars, and can also be used to classify other kavapreparations and products. However, this classification does not helpwith distinguishing the neuroactive effects of the different kavacultivars. In order to better distinguish the neuroactive effects ofkava products, a two-dimensional logarithmic coordinate system ispresented which maps the concentrations of the neuroactive kavalactonesthat cross the blood-brain barrier the fastest: K, DHK, Y and DMY. TheY/DMY ratio defines the “X-axis” for this coordinate system and theDHK/K ratio defines the “Y-axis”. The logarithmic nature of thecoordinate system comes from the fact that the DHK/K and Y/DMYconcentration ratios are in dB's, which means 10*LOG₁₀(DHK/K) and10*LOG₁₀(Y/DMY). A point centered on the origin (0,0) signifies that theDHK/K and Y/DMY ratios are both 1. Positive values reflect ratiosgreater than 1, and negative values correspond to ratios less than 1.

[0042]FIG. 3 is a map of average DHK/K vs. Y/DMY concentration ratios(in dB) for 1) lateral roots of the five different usage classes ofVanuatu kava cultivars, 2) lateral roots of 26 Fijian kava cultivars, 3)Alden Botanica's Essence of Kava (or EoK) extract of Vanuatu kava, and4) Schwabe's Laitan kava extract. The DHK/K vs. Y/DMY map in FIG. 3 iseffective in separating the five classes of Vanuatu kava cultivars, theFijian kava cultivars, EoK, and Laitan. The average for the Fijian kavasfalls in the fourth quadrant (DHK<1 and Y/DMY>1), in contrast to theaverages for the D, C, M, and T Vanuatu kava cultivars in the firstquadrant (DHK>1 and Y/DMY>1), and the average for the N Vanuatu kavacultivars in the second quadrant (DHK>1 and Y/DMY<1). Although EoK ismade from Vanuatu kava, the composition is about 20% lateral roots and80% rhizome. The high percentage of rhizome in EoK could explain why itsDHK/K ratio is less than 1 because K tends to dominate in the rhizome.The M%+DHM% for EoK is 21%, which is characteristic of a Vanuatu Dailykava. The lateral root and rhizome compositions in Laitan are not known,and so it is difficult to suggest a reason for its DHK/K vs. Y/DMYmapping. However, its M%+DHM% of 34% is closer to the average M%+DHM%for Vanuatu Custom, Medicinal and/or Two-day kava cultivars and theaverage for Fijian kava cultivars. The high M%+DHM% of Laitan relativeto that for EoK implies that Laitan will have a more muscle relaxingeffect and a higher probability of inducing nausea.

[0043] As will be appreciated, there are many kava cultivars thatcontain kavalactone distributions which are not well suited forconsumption. In order to generate a kava product, such as a paste or adry flowable powder for use in fast dissolve tablet and otherapplications, raw kava root is processed to produce a kava paste, oil orresin (collectively referred to herein as “paste”) that contains thekavalactones in the desired proportions, such as a distribution profilethat corresponds to the most preferred Vanuatu one day cultivars. Thepaste can then be further processed, e.g., to produce a refined pasteand/or a flowable powder. Preferred techniques are discussed below.These products generally can be referred to as a processed kavaproducts.

[0044] As an initial step, the kava itself must be harvested, dried, andground to size. The active kavalactones are most prevalent in thelateral roots of the plant. Various different cultivars areconventionally used, including but not limited to Isa, Mahakea, Moi,Papa Eleele, Borogu, Ahine, Kelaï, Palisi, Puna Green, Hanakapiai, Hiwa,Spotted Hiwa, Nene, SIG, Apu Awa, Alia, Melomelo, and Pia. Each cultivarhas a typical concentration of the various kavalactones resulting indifferent effects from ingesting the root or a root extract. Theharvested roots are preferably dried to a moisture content of between 3%and 10%, most preferably around 5%, and then ground to a particle sizesuitable for subsequent processing. A typical particle size is betweenabout 60 mesh to about 300 mesh, which correlates to about 250μ to about50μ, respectively, and preferably to between about 110μ and about 75μ.

[0045] The powdered kava root is then processed to produce a kava pasteusing techniques described below. In a preferred technique, the kava isprocessed using CO₂ in the liquid phase, but supercritical phase CO₂extraction can be used. A solvent modifier, such as ethyl alcohol orrefrigerant chemicals, can be added. Preferably, prior to the primaryextraction steps, the feedstock is initially processed by subjecting itto a high pressure carbon dioxide environment followed by a rapiddecompression. This compression-decompression process advantageouslyresults in a substantially higher kavalactone yield than achievedwithout the decompression step.

[0046] The paste can then be further processed to produce a flowablepowder. Although a paste made according to the present invention ispreferably used, kava pastes produced using various alternativetechniques can alternatively be used. Such methods include thosedisclosed in Published PCT Application WO 00/72861 to Martin et al.entitled “Pharmaceutical Preparations of Bioactive Substances Extractedfrom Natural Sources” and in U.S. Pat. No. 5,512,285 to Wilde entitled“Fragrance Extraction,” the entire contents of which are both expresslyincorporated by reference.

[0047] In a specific implementation of the method for producing the kavapaste, the powdered dried root is placed in a stainless steel vessel andpreprocessed by pressurizing the vessel with CO₂ to between about 1100psi and about 4500 psi, preferably at least about 1800 psi, at atemperature of between about 10° C. and about 60° C., and preferablybetween about 15° C. and about 20° C. It is not required that thepressures reach the critical point of CO₂ (1100 psi and 31° C.) duringthis stage. After the desired pressure is reached and held for a periodof time, ranging from continuous flow to fill and hold, where the holdtime can vary from between about 5 minutes to about 60 minutes, thepressure in the extraction vessel is rapidly and substantially reduced,preferably to a level at or near one atmosphere. This preprocessing,while not necessary, allows for a higher efficiency of extraction in thesubsequent processing steps.

[0048] As noted above, various extraction steps can be used to preparethe refined kava paste from a starting material. The particulartechniques and solvents used are selected, to some extent, based on themoisture content present in the feedstock and on user preference. Aspecific factor that should be considered is the relative concentrationsof the various kavalactones that is desired in the final product. Forexample, it can be beneficial to substantially reduce the amount ofparticular kavalactones in the extract which may cause interaction withvarious prescription drugs or cause various negative effects, whileretaining high relative percentages of other kavalactones.

[0049] After the preferred decompression processing step is performed,the root contained within the stainless steel vessel is then processedto produce the kava extract paste. Various extraction processes (with orwithout the decompressive preprocessing) can preferably be used, withliquid CO₂ being the most preferred technique. The processes arepreferably used in the alternative but two or more processes could becombined if desired. The processes are:

[0050] (1) CO₂ in the supercritical fluid phase.

[0051] (2) CO₂ in the liquid phase.

[0052] (3) CO₂ in the supercritical phase in combination with addedethyl alcohol as a modifier which is added in the range of 2% to 15%,and preferably between 2% and 10% based on the total mass.

[0053] (4) CO₂ in the liquid phase in combination with ethyl alcohol asa modifier which is added in the range of 2% to 15% and preferablybetween 2% and 10% based on the total mass.

[0054] (5) Refrigerant chemicals such as hydrofluorocarbons (HFCs),hydrochlorofluorocarbons (HCFCs), and/or chlorofluorocarbons (CFCs) suchas: HFC-23, HFC-32, HFC-125, HFC-134a, HFC-143a, HFC-152a, R-404a,R-407c, R-410a, HCFC-22, HCFC-123, HCFC-141b, HCFC-142b, R-502, R-11,R-12, and R-113. A more complete listing of suitable refrigerantchemicals is in Table 2. These refrigerants are widely available fromvarious chemical manufacturers and suppliers.

[0055] The selection of one extraction procedure over another depends onthe objectives of the extraction, the kavalactone concentration profileof the raw starting material and the desired concentration profile ofthe extract end product. In order to extract the largest quantity ofkavalactones in the aggregate, supercritical CO₂ extraction generallyprovides the best results. To alter or adjust the kavalactone profile,liquid CO₂ extraction techniques are more suitable. However, a carefullycontrolled supercritical CO₂ process may also be used. A gaseous CO₂process may also be suitable under certain circumstances.

[0056] For example, if a starting kava feedstock has a kavalactoneconcentration profile (specified as weight percentages of the individualkavalavctones) that is relatively low in (K+DHK) and relatively high inboth (M+DHM) and (DMY+Y), and a kava product is desired that isrelatively high in (K+DHK) and relatively low in both (M+DHM) and(DMY+Y), then the CO₂ extraction in the liquid phase becomes thepreferred process. The figures discussed below illustrate how liquid CO₂extraction transformed the kavalactone concentration profile of thestarting materials. In summary, the above extraction procedures providemaximum flexibility in starting with any kava raw product to obtain andextract end product with a specific kavalactone concentration profile.

[0057] In a first embodiment of the process, CO₂ is used in thesupercritical phase to perform the extraction step. The pressure is heldat a pressure and temperature regime that between about 1100 psi andabout 8000 psi and at a temperature between about 31° C. and about 80°C. During the process the extractable material is collected within astainless steel collection vessel that could be the same one as thatused in the first “low pressure” extraction step, and the supercriticalCO₂ can either be recycled for future use or vented into the atmosphere.The solvent-to-feed ratio increases as the pressure and temperature ofthe supercritical CO₂ is lowered. It has been found that when thematerial is processed at a pressure of about 8000 psi and a temperatureof about 80° C., all extractable material is obtained after asolvent-to-feed ratio of 8 is achieved.

[0058] In a second, most preferred, embodiment, CO₂ in the liquid phaseis used to perform the extraction step. Since the CO₂ is in the liquidphase, the extraction temperature can not exceed about 31° C., howeverthe pressure can rise to about 8000 psi. Conversely, the pressure can bemaintained below about 1100 psi and the temperature can be varied fromabout 5° C. up to about 70° C. During this process the extractablematerial is collected within the stainless steel collection vessel(which could be the same one as that used in a first “low pressure”extraction step). The liquid CO₂ can either be recycled for future useor vented into the atmosphere.

[0059] In a particular example of liquid CO₂ extraction andfractionation, CO₂ at a pressure between about 1100 and about 1800 psiis used at a temperature of between about 5° C. and about 20° C. The lowtemperature during extraction is controlled via a recirculating chillerplumbed to jacketed extractors, and the pressure within the extractionvessel is controlled via a back pressure regulator. Because ofpreferential absorption, and as discussed more fully below with respectto FIGS. 4-7, the kavalactone profile of the dissolved kava can besubstantially different from the profile of the source kava.

[0060] The extract-laden fluid emanating from the extractor is thencollected. A single collection vessel can be used or the fluid can besequentially processed using multiple collecting vessels to allow forfurther refinement of the kava extract. In a particular example, theliquid is first heated, e.g., by using a heat exchanger, to atemperature between about 30° C. and about 37° C. The vessel into whichthe fluid is deposited is also maintained at the same temperature. Avalve, such as a back pressure regulator situated just upstream of thecollection vessel, can be used to allow the fluid to flow into thevessel at the set pressure. An additional back pressure regulatorsituated at the outlet of the first collection vessel can be used tomaintain the first collection vessel at a pressure lower than that ofthe incoming fluid.

[0061] Maintaining the first collection vessel at a pressure of betweenabout 1000 to about 1200 psi introduces a 100 psi to 800 psi pressuredrop in the collection vessel relative to the fluid entering thecollection vessel. The increase in temperature and decrease in pressurecreates conditions that are not conducive to keeping the kavalactones,and kavain and dihydrokavain in particular, in solution. As a result,the kavalactones precipitate out of solution and can be collected in thecollection vessel.

[0062] A second and third collection vessel can be situated in serieswith the first collection vessel such that a generally constant pressurein the two vessels of between about 1000 psi and about 1200 psi ismaintained. However the temperature of each collection vessel increasesso that, for example, the second collection vessel is maintained at atemperature above that of the first collection vessel, such as betweenabout 35° C. and about 45° C., and the third collection vessel ismaintained at a temperature above that of the second collection vessel,such as between about 40° C. and about 50° C.

[0063] In a third embodiment, CO₂ is used in the supercritical phase toperform the second extraction step with the addition of ethyl alcohol asa solvent modifier. The conditions are maintained identical to thatdescribed in (1) with the addition of ethyl alcohol at about 2% to about15% and preferably between about 2% and about 10% of ethyl alcoholcontent by total mass. During the process the extractable material iscollected within a stainless steel collection vessel which can be thesame vessel as used in the first “low pressure” preprocessing step, andthe supercritical CO₂ can either be recycled for future use or ventedinto the atmosphere. In this embodiment the extract will contain ethylalcohol that can be removed in subsequent processing steps. The additionof ethyl alcohol increases the polarity of the solvent, resulting inenhanced extraction of the kavalactones with higher polarity, such asmethysticin and dihydromethysticin, relative to the other kavalactonesin the source material.

[0064] In a fourth embodiment, the conditions are generally the same asin the third embodiment but liquid CO₂ is used instead of supercriticalCO₂.

[0065] In a fifth embodiment, refrigerant chemicals, such as HFCs,HCFCs, and CFCs, are used in the liquid phase to perform the extractionstep. A selection of suitable HFCs, HCFCs, and CFCs appears in Table 2.During the extraction, the refrigerant chemical(s) are maintained in theliquid state and the pressure is kept below about 400 psi. Because ofthe comparatively low pressure, the extraction is varied primarily bytemperature. Preferably, the temperature is maintained at between about20° C. and about 70° C. and, in order to ensure suitable control andpredictability, to within about ±0.1° C. of a target temperature. Therefrigerant chemicals pass through the stainless steel extraction vesselcontaining the powdered root material and the extract-laden liquid isdeposited into a stainless steel collection vessel (which can be thesame one as that used in the preprocessing step). The refrigerantchemical of choice can be reclaimed via collection of the refrigerantchemical in its vapor state and subsequent pressurization into theliquid state. This is, in effect, a distillation process that leavesbehind the root extract while recovering the refrigerant chemical as aliquid. The refrigerant chemical can then be re-cycled through the samemass of powdered root to repeat the process until all extractablematerial is removed from the powdered root or, leveraging changes intemperature and extraction solvent, until the extract has a desiredkavalactone concentration.

[0066] The above-discussed processing steps will produce a kava rootextract as a viscous oil, resin, or paste. According to one aspect ofthe invention, the preferential and/or differing rates of extraction ofthe various kavalactones in the feedstock for different solvents andextraction methods can be leveraged to produce a final refined kavaproduct that has a relative kavalactone concentration meeting predefinedspecifications, even when those specifications may differ considerablyfrom the concentrations present in the input kava feedstock.

[0067] Multiple extraction steps can be performed. In addition, andalthough not necessary, extraction can also be performed during thecompression-decompression preprocessing step to selectively altervarious kavalactone concentrations.

[0068] According to a particular aspect of the invention, an improvedpaste extract can be produced by performing an additional extractionstep comprising use of supercritical CO₂ as a mobile phase combined withan adsorbent material such as that used for solid-phase extractions(SPE) and/or diatomaceous earth. The bonded materials used as silicasorbents include but are not limited to: C18 (Octadecyl), C8 (Octyl), C2(Ethyl), CH (Cyclohexyl), PH (Phenyl), and CN (End-capped Cyanopropyl).In operation, the extract paste material obtained by the initialprocessing, such as via the methods discussed above, is mixed with theSPE bonded phase in a ratio of about 5:1 to about 1:1 (SPE bonded phaseto root extract) by mass to produce a mixture having a doughyconsistency. The mixture is then placed in an extraction vessel.Fractions can then be collected over time by pressurizing the vessel tobetween about 1100 psi and about 8000 psi and a temperature betweenabout 31° C. and about 80° C. The material that elutes from thisfractionation can be segregated from each other by using multiplestainless steel collection vessels. Each fraction will generally have adifferent percentage of kavalactones, as well as a unique distributionof kavalactones that is distinct from that seen in the original rootmaterial. Typically, the percentages of kavain and dihydrokavain areincreased relative to the other kavalactones in the extract.

[0069] As will be appreciated, the time during which a solvent isallowed to flow over the kava feedstock can also effect the ratio of thefinal product since, for example, even a solvent that extracts aparticular kavalactone slowly may eventually extract all of thatkavalactone if sufficient time has passed. The particular amount of timeto allow the solvent to operate before extraction of dissolved materialfrom the solvent begins is dependent on the kavalactone distribution ofthe feedstock, the different rates at which the solvent extracts each ofthe kavalactones, and the desired kavalactone profile of the kavaextract. Given the information presented herein, one of ordinary skillin the art, using only routine experimentation can select an appropriatetime to terminate the extraction process.

[0070] The composition of a kava product can be described in a varietyof ways. In accordance with the present invention, several parametersare defined which can be used to describe the composition of a kavaextract:

[0071] 1) Combined weight percentage of the six major alpha-pyrones:methysticin (M), dihydromethysticin (DHM), yangonin (Y),desmethoxyyangonin (DMY), kavain (K), and dihydrokavain (DHK);

[0072] 2) Combined weight percentage of M and DHM;

[0073] 3) Combined weight percentage of DHK and K;

[0074] 4) Combined weight percentage of Y and DMY;

[0075] 5) Ratio of the weight percentages of Y and DMY, i.e., Y/DMY;

[0076] 6) Ratio of the weight percentages of DHK and K, i.e., DHK/K;

[0077] 7) Combined weight percentage of flavokavain A and flavokavain B.

[0078] The first property is a rough indicator of the potency of theextract, e.g., if the extract has 0% total kavalactones it has nopotency, and if it has 100% total kavalactones it is very potent.Properties 2-6 combine to define whether the kava extract can beclassified in the “Daily” or “non-daily” categories, such as“Two-Day”and “No Drink”. Property 7 is an indicator of the amount offlavokavains in the extract, Flavokavains are flavanoids specific to thekava plant. Flavanoids in general are anti-oxidants.

[0079] A most preferred kavalactone distribution for a kava extract,such as in a kava paste or a dry flowable power for use in oral deliveryhas a combination of the following properties:

[0080] 1) Total weight percentage of M+DHM+Y+DMY+DHK+K ranges from aminimum of about 20% to a maximum of about 90%;

[0081] 2) Combined M+DHM weight percentage ranges from a minimum ofabout 15% or lower to a maximum of about 29%;

[0082] 3) Combined weight percentage of DHK and K ranges from a minimumof about 50% to a maximum of about 70%-80%;

[0083] 4) Combined weight percentage of Y and DMY ranges from a minimumof about 5% to a maximum of about 25%;

[0084] 5) Ratio of Y weight percentage to DMY weight percentage,expressed as the logarithmic function 10*LOG₁₀(Y/DMY) in dB units,ranges from a minimum of about −1 to a maximum of about 2;

[0085] 6) Ratio of DHK weight percentage to K weight percentage,expressed as the logarithmic function 10*LOG₁₀(DHK/K) in dB units,ranges from a minimum of about −4 to a maximum of about 1; and

[0086] 7) Combined weight percentage of flavokavain A and flavokavain Branges from a minimum of about 0.3% to a maximum of about 3%.

[0087] The value of these properties for a sample of a processed kavaproduct can be determined using conventional analytical techniques, suchas HPLC-UV-S (High Performance Liquid Chromotography with Ultra-Violetdetection (254 nm) and Chemical Standards), or HPLC-Electrospray-MassSpectrometry.

[0088] Property 1 indicates that in order to have a potent product, suchas a tablet, it should have a minimum of about 20% kavalactones byweight, and a maximum of about 90% kavalactones by weight. Property 7indicates that the weight percentage of the flavokavains should be about0.3% to about 3%, which values are typical for unprocessed kava.However, in conventional processed kava extracts, the flavokavains tendto be removed, either deliberately or due to processing effects.

[0089] Properties 2-4 combine to define extracts with a kavalactonedistribution typical of a “Daily” kava cultivar found in Vanuatu.Properties Attributes 2, 5 and 6 also combine to define extracts with akavalactone distribution typical of a “Daily”kava cultivar found inVanuatu. The range of properties 2-7 are taken from the values measuredfor “Daily” kava cultivars found in Vanuatu.

[0090] According to a preferred particular embodiment, a processed kavaproduct produced according to the invention comprises less than about15% of the combination of methysticin and dehyromethysticin, less thanabout 8% of the combination of yangonin and desmethooxyyangonin, andgreater than about 70% of the combination of kavain and dihydrokavain. Asimilar kavalactone composition comprises up to about 7% methysticin, upto about 5% dehyromethysticin, up to about 1% yangonin, up to about 4%desmoxyyangonin, and greater than about 38% kavain.

[0091] In an alternative embodiment, the product is not limited to theproduction method discussed heretofore. For instance, the product may besynthetically produced by combining the individual kavalactones in theirdesired weight ratios. In this embodiment, the resulting materialpreferably has a kavalactone profile having at least one of thefollowing characteristics: a) a combined weight percentage of M and DHMless than about 15% of the total weight of the profile, b) a combinedweight percentage of DMY and Y less than about 8% of the total weight ofthe profile and c) a combined weight percentage of K and DHK greaterthan about 70% by weight of the kavalactone profile. In this embodiment,M is less than about seven percent by weight of the kavalactone profile,DHM is less than about five percent by weight of the kavalactoneprofile, DMY is less than about four percent by weight of thekavalactone profile, Y is less than about one percent by weight of thekavalactone profile, DHK is greater than about fifty percent by weightof the kavalactone profile or K is greater than about thirty-eightpercent by weight of the kavalactone profile. Specifically, a) M is inthe range of about 2.6 percent to about 4.8 percent by weight of saidkavalactone profile; b) DHM is in the range of about 8.7 percent toabout 13 percent by weight of said kavalactone profile; c) K is in therange of about 28 percent to about 39 percent by weight of saidkavalactone profile; d) DHK is in the range of about 30 percent to about52.4 percent by weight of said kavalactone profile; e) Y is in the rangeof about 0 percent to about 1.4 percent by weight of said kavalactoneprofile; and f) DMY is in the range of about 8.4 percent to about 11.8percent by weight of said kavalactone profile. Furthermore, thismaterial may have a kavalactone profile with a ratio of DHK to K byweight of less than about 4 dB or a ratio of Y to DMY by weight of lessthan about −5 dB.

[0092] The material described herein may also be characterized as havinga kavalactone profile as follows: a) a combined weight of M and DHM lessthan about 20% of the kavalactone profile, a combined weight of Y andDMY less than about 56% and the combined weight of DMY and Y is presentin a weight percentage equal to about −2.78 multiplied by the weightpercentage of the combined weight of M and DHM plus about 56%; b) acombined weight of M and DHM less than about 60% of the kavalactoneprofile, a combined weight of Y and DMY less than about 13% and thecombined weight of DMY and Y is present in a weight percentage equal toabout −0.22 multiplied by the weight percentage of the combined weightof M and DHM plus about 60%; or c) a combined weight of M and DHM lessthan about 64% of the kavalactone profile, a combined weight of K andDHK less than about 79% and the combined weight of K and DHK is presentin a weight percentage equal to about −1.23 multiplied by the weightpercentage of the combined weight of M and DHM plus about 79%. Finally,the material described herein may be characterized as having akavalactone profile having a weight ratio of K to DHK less than about−4.313 multiplied by the weight ratio of Y to DMY minus about 10 dB.

[0093] In the extraction methods discussed above, the desiredkavalactones were extracted from a source material, such as ground kavaroot or a pre-processed kava paste, and the remainder contained theundesirable materials. The opposite technique can also be used. Inparticular, a kava source material can be processed using a solvent thatpreferentially extracts undesired kavalactones, such as methysticin anddehyromethysticin, faster than other, more desired kavalactones. Thematerial remaining in the extraction vessel would then be collected andcold have the desired altered kavalactone profile. It has beendetermined that the extraction rate of methysticin and dehyromethysticinincreases with increasing polarity of the extract and that certainrefrigerant solvents, such as R22, can extract these undesirablekavalactones at a sufficiently greater rate than remaining kavalactonesto allow this alternative refinement technique to be used. The specificextraction environments, rates of extraction, and solvent used dependson the starting profile of the source material and the degree of profilechange desired. Specific solvent and environmental attributes can bedetermined by those of ordinary skill in the art using no more thanroutine experimentation typical for adjusting a process to account for,e.g., variations in the attributes of starting materials that is to beprocessed to produce an output material that has specified attributes.

[0094] A kava paste extract, such as discussed above, can be processedto produce consumable items, for example, by mixing it in a food productor in a capsule, or providing the paste itself for use as a dietarysupplement, with sweeteners and flavors added as appropriate. However, apaste extract of this type can be difficult to process because it doesnot flow well and may therefore not be well suited for processing byvarious types of high speed machinery.

[0095] According to a further aspect of the invention, the kava pasteextract discussed above (or a kava paste produced using othertechniques) can be further processed to produce a dry, flowable kavapowder. The powder can be used as a dietary supplement that can be addedto various edible products. The powder is also suited for use in a rapiddissolve tablet.

[0096] According to a particular aspect of the invention, the kavaextract powder is produced to have a kavalactone distribution that isparticularly well suited for delivery in the oral cavity of humansubjects, e.g., via a rapid dissolve tablet. Preferably, the desireddistribution properties are achieved by adjusting the extraction processto take advantage of the differing extraction rates of the variouskavalactones according to type of extraction method and the operatingparameters used. Although this technique may not result in an extractthat contains substantially all of the kavalactones from a sample (as isthe goal of conventional extraction processes), the desired ratios canbe achieved without having to perform extraction of individualkavalactones, e.g., through chromatography, and then a subsequentrecombination of the individual extracts.

[0097] In one embodiment of a method for producing the kava powder, theextract paste is mixed with a suitable solvent, such as ethyl alcohol orwater, along with a suitable food-grade carrier material, such asmaltodextrin, dextrose, or starch and the mixture is spray air-driedusing conventional techniques to produce a powder having grains of verysmall kava extract particles combined with the food-grade carriermaterial.

[0098] In a particular example, a kava extract paste, preferably about60% to about 80% total kavalactones by weight, is mixed with about twiceits weight of a food-grade carrier, such as maltodextrin having with anaverage particle size of between about 100 to about 150 micrometers andan ethyl alcohol solvent using a high shear mixer. Inert carriers, suchas silica, preferably having an average particle size on the order ofabout 1 to about 50 micrometers, can be added to improve the flow of themixture. Preferably, such additions are up to about 2% by weight of themixture. The amount of ethyl alcohol used is preferably the minimumneeded to form a solution with a viscosity appropriate for sprayair-drying. Typical amounts are in the range of between about 5 to about10 liters per kilogram of paste. The solution of kava extract,maltodextrin and ethyl alcohol is spray dried to generate a powder withan average particle size comparable to that of the starting carriermaterial and a kavalactone content of about 20% to about 35% by weight.

[0099] In a second embodiment, the kava extract paste and a food-gradecarrier, such as magnesium carbonate, a whey protein, or maltodextrin,are dry mixed, followed by mixing in a high shear mixer containing asuitable solvent, such as ethyl alcohol or water. The mixture is thendried via freeze drying or refractive window drying. In a particularexample, kava extract paste comprising on the order of about 60% toabout 80% total kavalactones by weight is combined with about one andone-half times by weight of the paste of a food-grade carrier, such asmagnesium carbonate, having an average particle size of about 20 toabout 100 micrometers. Inert carriers, such as silica, and preferablyhaving an average particle size of about 1 to about 50 micrometers canbe added, preferably in an amount up to 2% by weight of the mixture, toimprove the flow of the mixture. The magnesium carbonate and silica arethen dry mixed in a high-speed mixer, similar to a food processor-typeof mixer, operating at 100's of rpm. The kava extract paste then isheated until it flows like a heavy oil. Preferably, it is heated to atleast about 50° C. The heated kava paste/oil is then added to themagnesium carbonate and silica powder mixture that is being mixed inmixer.

[0100] The mixing of the kava paste/oil and the magnesium carbonate andsilica is continued preferably until the particle sizes are in the rangeof between about 250 micrometers to about 1 mm. Between about two to tenliters of cold water (preferably at about 4° C.) per kilogram of pasteis introduced into a high shear mixer. The mixture of kava extractpaste, magnesium carbonate and silica is the introduced slowly orincrements into the high shear mixer while mixing. An emulsifying agent,such as carboxymethylcellulose can also be added to mixture if needed.Sweetening agents can also be added at this stage if desired, such as upto about 5% by weight. Alternatively, extract of Stevia rebaudiana, avery sweet-tasting dietary supplement, can be added instead of, or inconjunction with, a specific sweetening agent. (For simplicity, Steviawill be referred to herein as a sweetening agent.) After mixing iscompleted, the mixture is dried using freeze-drying or refractive windowdrying. The resulting dry flowable powder of kava extract, magnesiumcarbonate, silica and optional emulsifying agent and optional sweetenerhas an average particle size comparable to that of the starting carriermaterial and a kavalactone content of about 20% to about 35% by weight.

[0101] According to another embodiment, kava extract paste that is onthe order of about 60% to about 80% total kavalactones by weight iscombined with approximately an equal weight a food-grade carrier, suchas whey protein, preferably having an average particle size of betweenabout 200 to about 1000 micrometers. Inert carriers, such as silicapreferably having an average particle size of between about 1 to about50 micrometers, or carboxymethylcellulose, preferably having an averageparticle size of between about 10 to about 100 micrometers, can be addedto improve the flow of the mixture. Preferably, this addition is no morethan about 2% by weight of the mixture.

[0102] The whey protein and inert ingredient are then dry mixed in afood processor-type of mixer that operates at 100's of rpm. The kavaextract paste is heated until it flows like a heavy oil. Preferably, itis heated to at least 50° C. The heated kava paste/oil is then added tothe whey protein and inert carrier that is being mixed in the foodprocessor-type mixer. The mixing of the kava paste/oil and the wheyprotein and inert carrier is continued until the particle sizes are inthe range of about 250 micrometers to about 1 mm. Next, 2 to 10 literscold water (preferably about 4C) per kilogram of paste is introducedinto a high shear mixer. The mixture of kava extract paste, whey proteinand inert carrier is preferably introduced slowly or in incrementalamounts with the high shear mixer while mixing. Sweetening agents orother sweet-tasting additives of up to about 5% by weight, such asStevia, can be added at this stage if desired.

[0103] After mixing is completed, the mixture is dried usingfreeze-drying or refractive window drying. The resulting dry flowablepowder of kava extract, whey protein, inert carrier and optionalsweetener has an average particle size of about 150 to about 700micrometers and a kavalactone content of about 20% to about 35% byweight.

[0104] In a third embodiment, the kava extract paste is dissolved in asupercritical fluid, which is then adsorbed onto a suitable food-gradecarrier, such as maltodextrin, dextrose, or starch. Preferably,supercritical CO₂ is used as the solvent. Specific examples includestarting with a kava extract paste that is on the order of about 60% toabout 80% total kavalactones by weight and adding from 1 to one one-halftimes the paste by weight of a food-grade carrier, such as maltodextrin,and having an average particle size of between about 100 to about 150micrometers. This mixture is placed into a chamber containing mixingpaddles and which can be pressurized and heated. The chamber ispressurized with CO₂ to a pressure in the range of between about 1100 toabout 8000 psi and set at a temperature in the range of between about20° to about 100° C. The exact temperature and pressure is selected toplace the CO₂ in a supercritical fluid state.

[0105] Once the CO₂ in the chamber is in the supercritical state, thekava extract paste is dissolved. The mixing paddles agitate the carrierpowder so that it has intimate contact with the supercritical CO₂ thatcontains the dissolved kava extract paste. The mixture of supercriticalCO₂, dissolved kava extract paste and the carrier powder is then ventedthrough an orifice in the chamber so that it undergoes explosivedecompression into a collection vessel which is at a pressure andtemperature that does not support the supercritical state for the CO₂.The CO₂ is thus dissipated. The resulting powder in the collectionvessel is the carrier powder impregnated with the kava extract paste.The powder has an average particle size comparable to that of thestarting carrier material and a kavalactone content of between about 20%to about 40% by weight. The resulting powder is dry and flowable. Ifneeded, the flow characteristics can be improved by adding inertingredients to the starting carrier powder, such as silica at up toabout 2% by weight as discussed above.

[0106] Once a dry kava powder is obtained, such as by the methodsdiscussed herein, it can be distributed for use, e.g., as a dietarysupplement or for other uses. In a particular embodiment, the powder ismixed with other ingredients to form a tableting composition of powderwhich can then be formed into tablets. In a particular embodiment, thetableting powder is first wet with a solvent comprising alcohol, alcoholand water, or other suitable solvents, in an amount sufficient to form athick doughy consistency. Suitable alcohols include, but are not limitedto, ethyl alcohol, isopropyl alcohol, denatured ethyl alcohol containingisopropyl alcohol, acetone, and denatured ethyl alcohol containingacetone. The resulting paste is then pressed into a tablet mold. Anautomated molding system, such as described in U.S. Pat. No. 5,407,339can be used. The tablets are then removed from the mold and dried,preferably by air-drying for at least several hours at a temperaturehigh enough to drive off the solvent used to wet the tableting powdermixture, typically between about 70° to about 85° F. The tablets canthen be packaged for distribution.

[0107] A wide variety of tablet formulations can be made. Preferably,the tablet has a formulation that results in a rapid dissolution ordisintegration in the oral cavity. The tablet is preferably of ahomogeneous composition that dissolves or disintegrates rapidly in theoral cavity to release the kava extract content over a period of about 2seconds or less to about 60 seconds or more, preferably about 3 to about45 seconds, and most preferably between about 5 to about 15 seconds.

[0108] Various rapid-dissolve tablet formulations known in the art canbe used. Representative formulations are disclosed in U.S. Pat. Nos.5,464,632, 6,106,861, and 6,221,392, the entire contents of which areexpressly incorporated by reference herein. A particularly preferredtableting composition or powder contains about 10% to about 60% byweight of the kava extract powder and about 30% to about 60% of awater-soluble diluent. Suitable diluents include lactose, dextrose,sucrose, mannitol, and other similar compositions. Lactose is apreferred diluent but mannitol adds a pleasant, cooling sensation andadditional sweetness in the mouth. More than one diluent can be used. Asweetener can also be included, preferably in an amount of between about3% to about 40% by weight depending on the desired sweetness. Preferredsweetening substances include sugar, saccharin, sodium cyclamate,aspartame, and Stevia extract, used singly or in combination, althoughother sweeteners could alternatively be used. Flavorings, such as mint,cinnamon, citrus (e.g., lemon or orange), can also be included,preferably in an amount between about 0.001% to about 1% by weight.

[0109] Typically, the kava extract added to the tablet has a goldencolor and it is considered unnecessary to include additional colorings.However, if a coloring is desired, natural and/or synthetic colors canbe added, preferably in an amount of between about 0.5% to about 2% byweight.

[0110] Typically, this tableting composition will maintain its formwithout the use of a binder. However, if needed, various binders aresuitable and can be added in an amount of between about 5% to about 15%or as necessary. Preferred binders are acacia or gum arabic. Alternativebinders include sodium alginate, extract of Irish moss, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, VEEGUM®(available from R.T Vanderbilt Co., Inc. of Norwalk, Conn.), larcharabogalactan, gelatin, Kappa carrageenan, copolymers of maleicanhydride with ethylene or vinyl methyl ether.

[0111] A tablet according to this aspect of this invention typicallydoes not require a lubricant to improve the flow of the powder fortablet manufacturing. However, if it is so desired, preferred lubricantsinclude talc, magnesium stearate, calcium stearate, stearic acid,hydrogenated vegetable oils, and carbowax in amounts of between about 2%to about 10% by weight.

[0112] Similarly, a disintegrant is not expected to be necessary toproduce rapid dissolve tablets using the present tablet composition.However, a disintegrant can be included to increase the speed with whicha resulting tablet dissolves in the mouth. If desired, between about0.5% to about 1% by weight of a disintegrant can be added. Preferreddisintegrants include starches, clays, celluloses, algins, gums,crosslinked polymers (including croscarmelose, crospovidone and sodiumstarch glycolate), VEEGUM® HV, agar, bentonite, natural sponge, cationexchange resins, aliginic acid, guar gum, citrus pulp, sodium laurylsulphate in an amount of about 0.5% to about 1% of the total mass of thetablet.

[0113] It is also generally considered unnecessary to buffer the tabletcomposition. However, a buffer may be beneficial in specificformulations. Preferred buffering agents include mono- and di-sodiumphosphates and borates, basic magnesium carbonate and combinations ofmagnesium and aluminum hydroxide.

[0114] In a preferred implementation, the tableting powder is made bymixing in a dry powdered form the various components as described above,e.g., active ingredient (kava extract), diluent, sweetening additive,and flavoring, etc. An overage in the range of about 10% to about 15% ofthe active extract of the active ingredient can be added to compensatefor losses during subsequent tablet processing. The mixture is thensifted through a sieve with a mesh size preferably in the range of about80 mesh to about 100 mesh to ensure a generally uniform composition ofparticles.

[0115] The tablet can be of any desired size, shape, weight, orconsistency. The total weight of the kava extract in the form of a dryflowable powder in a single oral dosage is typically in the range ofabout 80 mg to about 600 mg. An important consideration is that thetablet is intended to dissolve in the mouth and should therefore not beof a shape that encourages the tablet to be swallowed. The larger thetablet, the less it is likely to be accidentally swallowed, but thelonger it will take to dissolve or disintegrate. In a preferred form,the tablet is a disk or wafer of about ⅛ inch to about ½ inch indiameter and about 0.2 inch to 0.08 inch in thickness, and has a weightof between about 160 mg to about 1,200 mg. In addition to disk, wafer orcoin shapes, the tablet can be in the form of a cylinder, sphere, cube,or other shapes. For example, the tablet can be formed into the generalshape of a kava plant leaf. Although the tablet is preferablyhomogeneous, the tablet may alternatively be comprised of regions ofpowdered kava extract composition separated by non-kava extract regionsin periodic or non-periodic sequences, which can give the tablet aspeckled appearance with different colors or shades of colors associatedwith the kava extract regions and the non-kava extract regions

[0116] An exemplary 250 mg tablet contains about 125.0 mg powdered kavaextract, about 12.5 mg extract of Stevia, about 35.5 mgcarboxymethylcellulose, and about 77.0 mg lactose. An exemplary 350 mgtablet contains about 160.0 mg powdered kava extract, about 15.0 mgextract of Stevia, about 15.0 mg acacia, and about 160.0 mg lactose.Other formulations are also possible.

[0117] Although the extraction techniques are discussed herein in termsof kava, it should be recognized that the disclosed techniques can beadapted for use in forming an extract, in the form of a dry flowablepowder or another form and containing compositions extracted from otherplant products, such as ginseng, cherry, lettuce, echinacea, mate, andareca. In addition, while the preferred rapid dissolved formulation isdisclosed herein in the context of kava extract, the formulation canalso be used to provide a rapid dissolve tablet containing additional orother active ingredients that can be provided in powder form, such asvarieties of ginseng, cherry, lettuce, echinacea, mate, and areca.

[0118] The present invention is furthermore characterized by thedistribution of the kavalactones (methysticin, dihydromethysticin,kavain, dihydrokavain, yangonin, and desmethoxyyangonin) being used asan additive to potentiate and/or enhance the action of therapeutics,pharmaceuticals, nutraceuticals, or botanical extracts such that a lowerdosage of the chosen therapeutic, pharmaceutical, nutraceutical, orbotanical extract can be used or administered as a dose. The masspercentage of the sum of the six kavalactones: methysticin,dihydromethysticin, kavain, dihydrokavain, yangonin, anddesmethoxyyangonin, in relation to the total mass that includes theparticular active ingredient (therapeutic, pharmaceutical,nutraceutical, or botanical extract) can be from about 0.1% to about 75%of the total mass. More preferably, the percentage range of the mass ofthe six kavalactones in relation to the total mass that includes theparticular active therapeutic, pharmaceutical, nutraceutical, orbotanical extract is from about 5% to about 35%.

[0119] Said botanicals useful herein include, but are not limited to:Areca catechu, Piper betel, Ptychopetalum olacoides, Ilexparaguariensis, Echinacea purpurea, Echinacea angustifolia, Echinaceapallida, Panax quinquefolius, Panax ginseng, Curcuma longa, Lactucavirosa, Lactuca indica, Zingiber officinalis, Salix purpurea, Salixdaphnoides, Prunus avium, Prunus cerasus, Pfaffia paniculata, Turneradiffusa, Epimedium species, Terrestris tribulus, Rhodiola rosea,Astragalus membranaceus, Eucommia ulmoides, Gastrodia elata, Passifloraincamata, Uncaria rhyncophylla, and coleus forskohlii.

[0120] The pharmaceuticals/therapeutics useful herein include, but arenot limited to: methylsulfonylmethane, smooth muscle relaxants forasthma medication, acetylsalicylic acid, and other non-steroidalanti-inflammatories, such as ibuprofen, acetominophen; cholinergicagonists including carbachol, bethanechol, methacholine, arecoline,muscarine, and pilocarpine; antimuscarinic agents including atropine andscolpolamine; sympathomimetic agents including dopamine, albuterol, andphentermine; adrenergic receptor blocking agents including phentolamine,tolazoline, propanolol, metoprolol, atenolol, and reserpine;neuromuscular blocking agents including benzoquinonium, gallamine andmetocurine; central nervous system drugs, anesthetics includingbenzocaine, procaine, lidocaine, nitrous oxide and halothane; hypnoticand sedative (anti-anxiety) drugs including pentobarbital, secobarbital,diazepam, halcion and meprobamate; anti-psychotic agents includingthorazine, vesprin, and prolixin and imiprimine; parkinsonism drugsincluding levodopa and deprenyl; asthma drugs including albuterol andtheophylline; opioid analgesics and antagonists including morphine,codeine and oxycodone; antiarrythmic and antihypertinsive agentsincluding quinidine and procainamide; vasodilators and organic nitrates.

[0121] Other active ingredients useful herein include, but are notlimited to Scutelleria baicalensis and other species in the genusscutelleria such as S. laterifolia, Valeriana officinalis, Rosemaryofficinalis, Matricaria chamomilla, Eschscholzia califomica, and Avenasativa.

EXAMPLES

[0122] The following examples are illustrative of the nature of thepresent invention and are not to be regarded as limiting.

Example 1

[0123] This example describes the preparation of a kava extract havingthe properties shown in FIGS. 1-4 (i.e., properties typical of a “Daily”kava cultivar from Vanuatu). This process can be varied as needed and inaccordance with the profile of the source kava and the desired kavaprofile of the extract.

[0124] About 30 lbs. of chopped and ground lateral roots of kava areadded to a 32 liter extraction vessel. Pre-cooled liquid carbon dioxide(the pressurized liquid carbon dioxide was passed through a heatexchanger that was maintained at 0° C.) was pumped through the vessel ata pressure of 1800 psi. The carbon dioxide expanded and flashed into agas, thus cooling the lateral root to approximately 10° C. The resultanttemperature equilibrium of the effluent flowing from the extractionvessel was between 5° C. and 20° C. Approximately 500 lbs. of liquidcarbon dioxide was passed through the lateral roots under pressure, butbelow the supercritical temperature. This extraction was high pressureliquid extraction. The extract laden liquid carbon dioxide was collectedin a vessel that was at atmospheric pressure.

[0125] FIGS. 1-4, respectively, are plots of (DHK%+K%) vs. (M%+DHM%),(DMY%+Y%) vs. (M%DHM%), (DMY%+Y%) vs. (DHK%+K%), and 10*LOG₁₀(DHK/K) vs.10*LOG₁₀(Y/DMY) for the appropriate values measured for “Daily”,Two-Day” and “No Drink” kava cultivars from Vanuatu. The plots show thechanges in the kavalactone profile introduced during processingaccording to the present invention. The plots show how the kavalactoneprofile of the processed product is shifted away from an undesirableprofile to a more desired profile.

[0126] More generally, FIGS. 1-4 show how a raw kava product with akavalactone distribution that is not typical of the preferred “Daily”kava can be processed to yield an extract with a kavalactonedistribution more typical of the “Daily” kava. Note that the processingmethod simultaneously changes all Properties 2-6, discussed above, aswell as increasing the total kavalactone weight percentage. In anoptional step, the extract laden liquid carbon dioxide was collectedinto a cascade of three different vessels that are maintained atdifferent temperatures and under pressures so as to further altered thekavalactone profile of the extract collected in each vessel.

Example 2

[0127] A common kava feedstock was processed and passed throughsequentially connected collection vessels containing differenttemperature and pressure environments to produce different extractionconditions. In particular, three vessels were used containing liquid,supercritcal and gaseous CO₂, respectively. The profile of the kavaextracts at each stage of processing compared with the profile of thesource. The first collection vessel was used for liquid CO₂ extraction.The vessel was pressurized to 1150 psi and maintained at 26.2° C. Theextraction was performed at 1200 psi and 7° C. The second collectionvessel was used for supercritical CO₂ extraction. The vessel waspressurized to 1150 psi and maintained at 33.5° C. The third collectorwas used for gaseous CO₂ collection. The collection vessel waspressurized to 850 psi and maintained between 20° C. and 30° C.

[0128] A comparison of the profile of the source feedstock and theprofile of the extracts is shown in table 3, below: TABLE 3 CHANGE INKAVALACTONE PROFILE (in percentages) Profile in 1^(st) Profile in 2^(nd)Profile in 3^(rd) Feed extraction extraction extraction Kavalactonestock vessel vessel vessel Methysticin (M) 19.7 13.9 4.8 2.6Dihydromethysticin 10.2 10.4 13.0 8.7 (DHM) Kavain (K) 22.5 41.8 39.028.0 Dihydrokavain (DHK) 12.7 10.9 30.0 52.4 Yangonin (Y) 22.7 5.8 1.40.0 Desmethoxyyangonin 12.3 17.3 11.8 8.4 (DMY)

[0129] There are three dramatic changes that have occurred. First, thecombined M+DHM content has dropped from 29.9% to as low as 11.3%.Second, the combined K+DHK content has increased from 35.2% to as highas 80.4%. Third, the yangonin content has dropped from 22.7% to anon-detected level, effectively 0.0%. As will be appreciated, a carefulchoice of the temperature and pressure for each collector will result incontrolled and preferential distributions of the kavalactones.

We claim:
 1. A method for enhancing the efficacy of an active ingredientin a human comprising: administering to said human a product comprising:a kavalactone component and an active ingredient, wherein said activeingredient is selected from the group consisting of a therapeutic, apharmaceutical, a nutraceutical and a botanical, and wherein saidkavalactone component comprises a methysticin component, adihydromethysticin component, a desmethoxyyangonin component, a yangonincomponent, a dihydrokavain component, and a kavain component, andwherein said kavalactone component is between about 0.1% to about 75%,by mass, of said product.
 2. The method of claim 1 wherein saidkavalactone component is present in an amount from about 5 to about 35%,by mass, of said product.
 3. The method of claim 1 wherein said activeingredient is selected from the group consisting of: Areca catechu,Piper betel, Ptychopetalum olacoides, Ilex paraguariensis, Echinaceapurpurea, Echinacea angustifolia, Echinacea pallida, Panaxquinquefolius, Panax ginseng, Curcuma longa, Lactuca virosa, Lactucaindica, Zingiber officinalis, Salix purpurea, Salix daphnoides, Prunusavium, Prunus cerasus, Pfaffia paniculata, Tumera diffusa, Epimediumspecies, Terrestris tribulus, Rhodiola rosea, Astragalus membranaceus,Eucommia ulmoides, Gastrodia elata, Passiflora incarnata, Uncariarhyncophylla, and coleus forskohlii.
 4. The method of claim 1 whereinsaid active ingredient is selected from the group consisting of:methylsulfonylmethane, acetylsalicylic acid, ibuprofen, acetominophen,carbachol, bethanechol, methacholine, arecoline, muscarine, pilocarpine,atropine, scolpolamine, dopamine, albuterol, phentermine, phentolamine,tolazoline, propanolol, metoprolol, atenolol, reserpine, benzoquinonium,gallamine, metocurine, benzocaine, procaine, lidocaine, nitrous oxide,halothane, pentobarbital, secobarbital, diazepam, halcion, meprobamate,thorazine, vesprin, prolixin imiprimine, levodopa, deprenyl, morphine,codeine, oxycodone, quinidine, procainamide, theophylline, vasodilatorsand organic nitrates.
 5. The method of claim 1 wherein said activeingredient is selected from the group consisting of Scutelleriabaicalensis, Scutelleria laterifolia, Valeriana officinalis, Rosemaryofficinalis, Matricaria chamomilla, Eschscholzia califomica, and Avenasativa.
 6. The method of claim 1 wherein said product is a dry flowablepowder.
 7. The method of claim 1 wherein said product is a pasteextract.
 8. The method of claim 1 wherein said product is a liquidextract.
 9. The method of claim 1 wherein said product is a rapiddissolve tablet.
 10. The method of claim 1 wherein said kavalactonecomponent has at least one of the following combinations: a firstcombination comprising a methysticin component and a dihydromethysticincomponent wherein said first combination is less than about fifteenpercent by weight of said kavalactone component; a second combinationcomprising a desmethoxyyangonin component and a yangonin componentwherein said second combination is less than about eight percent byweight of said kavalactone component; a third combination comprising akavain component and a dihydrokavain component wherein said thirdcombination is greater than about seventy percent by weight of saidkavalactone component.
 11. The method of claim 10 wherein saidmethysticin component is less than about seven percent by weight of saidkavalactone component.
 12. The material of claim 10, wherein saiddihydromethysticin component is less than about five percent by weightof said kavalactone component.
 13. The material of claim 10, whereinsaid desmethoxyyangonin component is less than about four percent byweight of said kavalactone component.
 14. The material of claim 10,wherein said yangonin component is less than about one percent by weightof said kavalactone component.
 15. The material of claim 10, whereinsaid dihydrokavain component is greater than about fifty percent byweight of said kavalactone component.
 16. The material of claim 10,wherein said kavain component is greater than about thirty-eight percentby weight of said kavalactone component.